Hydroxychloroquine Causes Early Inner Retinal Toxicity and Affects Autophagosome-Lysosomal Pathway and Sphingolipid Metabolism in the Retina

Hydroxychloroquine (HCQ) is an anti-malarial drug but also widely used to treat autoimmune diseases like arthritis and lupus. Although there have been multiple reports of the adverse effect of prolonged HCQ usage on the outer retina, leading to bull's-eye maculopathy, the effect of HCQ toxicity on the inner retina as well as on overall visual functions has not been explored in detail. Furthermore, lack of an established animal model of HCQ toxicity hinders our understanding of the underlying molecular mechanisms. Here, using a small clinical study, we confirmed the effect of HCQ toxicity on the inner retina, in particular the reduction in central inner retinal thickness, and established a mouse model of chronic HCQ toxicity that recapitulates the effects observed in human retina. Using the mouse model, we demonstrated that chronic HCQ toxicity results in loss of inner retinal neurons and retinal ganglion cells (RGC) and compromises visual functions. We further established that HCQ treatment prevents autophagosome-lysosome fusion and alters the sphingolipid homeostasis in mouse retina. Our results affirm the notion that HCQ treatment causes early damage to the inner retina and affects visual functions before leading to characteristic toxicity in the macular region of the outer retina, 'bull's-eye maculopathy.' We also provide insights into the underlying molecular mechanisms of HCQ retinal toxicity that may involve autophagy-lysosomal defects and alterations in sphingolipid metabolism.

Automated summary

This article investigates the toxic effects of hydroxychloroquine (HCQ) on the inner retina and its impact on visual functions. Through a clinical study and a mouse model, the researchers found that chronic HCQ toxicity results in the loss of inner retinal neurons and retinal ganglion cells, leading to compromised visual functions. They also provided insights into the underlying molecular mechanisms involving autophagy-lysosomal defects and alterations in sphingolipid metabolism.